{"doi":"10.1101/2021.05.10.442447","title":"Distinct states of proinsulin misfolding in MIDY","abstract":"Abstract A precondition for efficient proinsulin export from the endoplasmic reticulum (ER) is that proinsulin meets ER quality control folding requirements, including formation of the Cys(B19)-Cys(A20) “interchain” disulfide bond, facilitating formation of the Cys(B7)-Cys(A7) bridge. The third proinsulin disulfide, Cys(A6)-Cys(A11), is not required for anterograde trafficking, i.e., a “lose-A6/A11” mutant [Cys(A6), Cys(A11) both converted to Ser] is well secreted. Nevertheless, an unpaired Cys(A11) can participate in disulfide mispairings, causing ER retention of proinsulin. Among the many missense mutations causing the syndrome of Mutant INS gene-induced Diabetes of Youth (MIDY), all seem to exhibit perturbed proinsulin disulfide bond formation. Here we have examined a series of seven MIDY mutants [including G(B8)V, Y(B26)C, L(A16)P, H(B5)D, V(B18)A, R(Cpep+2)C, E(A4)K], six of which are essentially completely blocked in export from the ER in pancreatic β-cells. Three of these mutants, however, must disrupt the Cys(A6)-Cys(A11) pairing to expose a critical unpaired cysteine thiol perturbation of proinsulin folding and ER export, because when introduced into the proinsulin lose-A6/A11 background, these mutants exhibit native-like disulfide bonding and improved trafficking. This maneuver also ameliorates dominant-negative blockade of export of co-expressed wild-type proinsulin. A growing molecular understanding of proinsulin misfolding may permit allele-specific pharmacological targeting for some MIDY mutants.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":224202,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9495,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":651123,"name":"Anoop Arunagiri","orcid":"0000-0001-9839-1860","position":1,"is_corresponding":false},{"id":691871,"name":"Anis Hassan","orcid":null,"position":2,"is_corresponding":false},{"id":691872,"name":"Kaitlin Regan","orcid":null,"position":3,"is_corresponding":false},{"id":385298,"name":"Billy Tsai","orcid":"0000-0003-2859-1415","position":4,"is_corresponding":false},{"id":338985,"name":"Balamurugan Dhayalan","orcid":"0000-0001-6002-1207","position":5,"is_corresponding":false},{"id":338990,"name":"Michael A. Weiss","orcid":"0000-0003-1325-1610","position":6,"is_corresponding":false},{"id":289733,"name":"Ming Liu","orcid":"0000-0003-2665-4072","position":7,"is_corresponding":false},{"id":33730,"name":"Peter Arvan","orcid":"0000-0002-4007-8799","position":8,"is_corresponding":false},{"id":33712,"name":"Leena Haataja","orcid":"0000-0003-3701-4679","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-18T23:54:18.470602Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}